Budesonide pellets with a controlled released pattern and process for producing the same

ABSTRACT

Disclosed are budesonide pellets with a controlled release pattern containing, from the inside to the outside: a) neutral pellets; b) an active principle layer of micronized budesonide and one or more water-soluble auxiliaries; c) a first lacquer coating consisting of 80 to 97% of at least one lacquer insoluble in gastric fluids but soluble in intestinal fluids and 3 to 20% of at least one lacquer insoluble in both gastric and intestinal fluids; and d) a second lacquer coating consisting of at least one lacquer insoluble in gastric and intestinal fluids. The invention also relates to a process for producing budesonide pellets with a controlled release pattern.

This application is a 371 of PCT/EP941/02531 filed Jul. 29, 1994.

The invention relates to budesonide pellets with controlled releaseprofile and to a process for producing them. In particular, it relatesto budesonide pellets with a release-controlling membrane comprising twoseparate lacquer layers.

Budesonide (16a,17-butylidenedioxy-1b,21-dihydroxy-1,4-pregnadiene-3,20-dione) is ahighly active corticosteroid which has been shown to be extremelyeffective for the treatment of inflammatory processes of the middle andlower intestinal tract. Thus, budesonide in oral slow-release form hasbrought about remission of active Crohn's disease and has few sideeffects on adrenocortical function (cf. the pilot study in "DerKassenarzt, 13, pages 34 to 37, 1993"). A review of the pharmacologicalproperties and the therapeutic efficacy of budesonide for asthma andrhinitis is given in "Drugs 44 (3), 375-407, 1992". The absorption ofbudesonide is low and it is subject to extensive first-pass metabolism.Since inflammatory processes often affect relatively large sections ofthe intestinal tract, there is a demand for a pharmaceutical form whichspreads reproducibly over wide areas of the intestine and, moreover,releases the active substance only there.

An object of the invention is therefore to provide a pharmaceuticalcomposition which ensures optimal distribution of the small amount ofactive substance (1 to 3 mg/dose) at the site of inflammation.Furthermore, the active substance is to be released neither in thestomach nor in the duodenum or the proximal jejunum but only from themiddle jejunum onwards. From this section onwards there should berelatively rapid release (about 80 to 90% in 2 hours), differingdistinctly from a slow-release form (for example 90% release in 6 to 8hours).

Furthermore, a reproducible onset of action is to be ensured throughrapid passage of the pharmaceutical composition through the stomach.

After a release-controlling shell has been detached, the sparinglysoluble, very finely micronized active substance is to become rapidlyresuspended in the intestinal fluid and display its effect on theinflamed mucosa. It is furthermore intended to provide a process forproducing the pellets.

The invention is also in a process for producing budesonide pellets witha controlled release profile.

The various features of novelty which characterizes the invention arepointed out with particularity in the claims annexed to and forming apart of this specification. For a better understanding of the invention,its operating advantages and specific objects obtained by its use,reference should be had to the accompanying drawings and descriptivematter in which there is illustrated and described a preferredembodiment of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The FIGURE schematically depicts a flow diagram for a process forproducing the pellets of the invention.

This object is best achieved by pellets packed, for example, in hardgelatin capsules. After disintegration of the capsule in the stomachthey are expelled into the intestine in accordance with the motilityphase prevailing in the stomach at the time. This results in adistribution effect, and the active substance is able to display itseffect on larger areas of the intestinal mucosa than a single-dose form.

It has been found, surprisingly, that budesonide pellets with controlledrelease profile can be obtained when the active substance is envelopedby a release-controlling membrane comprising two separate lacquerlayers, one lacquer layer I consisting of 80 to 97% of lacquers whichare insoluble in gastric fluid and soluble in intestinal fluid and 3 to20% of lacquers which are insoluble in gastric and intestinal fluids,and a lacquer layer II consisting of 100% lacquers which are insolublein gastric and intestinal fluids.

The invention thus relates to budesonide pellets with controlled releaseprofile, which are characterized in that they comprise, from the insideto the outside,

a) neutral pellets

b) an active substance layer comprising micronized budesonide and one ormore water-soluble auxiliaries,

c) a lacquer layer I comprising 80 to 97% of lacquers which areinsoluble in gastric fluid and soluble in intestinal fluid and 3 to 20%of lacquers which are insoluble in gastric and intestinal fluids, in anamount of 4-16% by weight based on the lacquered active substancepellets (preferably 8-12%), and

d) a lacquer layer II consisting of 100% lacquers which are insoluble ingastric and intestinal fluids.

The invention furthermore relates to a process for producing budesonidepellets with controlled release profile, which is characterized in thatmicronized budesonide is suspended as active substance in a solventmixture consisting of alcohol:water from 0:100 to 20:80 with theaddition of one or more water-soluble auxiliaries, the suspension issprayed on to neutral pellets, after drying a lacquer suspension Iconsisting of 80 to 97% of lacquers which are insoluble in gastric fluidand soluble in intestinal fluid and 3 to 20% of lacquers which areinsoluble in gastric and intestinal fluids are sprayed on, and afterdrying a lacquer suspension II consisting of 100% lacquers which areinsoluble in gastric and intestinal fluids is sprayed on, and the activesubstance pellets are dried.

The pellets preferably comprise 75-95% by weight of neutral pellets,0.4-20% by weight of the active substance layer, 4-16% by weight (morepreferably 8-12% by weight) of lacquer layer I and 0.1-3% by weight(more preferably 0.5-1% by weight) of lacquer layer II, in each casebased on lacquered active substance pellets.

Lacquer layer I preferably comprises Eudragit L, Eudragit S, Eudragit RSand Eudragit RL, and lacquer layer II preferably comprises Eudragit Land Eudragit RS. Moreover, the content in lacquer layer I of Eudragit Lis 20 to 77%, preferably 40 to 50%, of Eudragit S is 20 to 77%,preferably 40 to 50%, of Eudragit RS, Eudragit RL is 3 to 20%,preferably 6 to 12%, where the total of Eudragit L and Eudragit S is 80to 97%. The content of Eudragit RL and Eudragit RS in lacquer membraneII is 100%, with the proportion of RL being 0-100% and of RS being100-0%.

The content of micronized budesonide per dose unit is 0.5-20 mg,preferably 0.5-5 mg, more preferably 0.6-3 mg. This corresponds to0.1-20% by weight, preferably 0.1-5% by weight, more preferably 0.2-3%by weight of budesonide, based on the lacquered active substancepellets. Moreover a dose unit contains about 150-750 individual pellets.The particle size of the micronized budesonide is 5 to 25 μp, preferablyabout 10 micrometers (μm).

In order to achieve high local concentrations of active substance andspread of the active substance over an area of inflamed intestine whichis as wide as possible, the dose of active substance has beendistributed over hundreds of independent release-controllingpharmaceutical forms (pellets) which are about 1 mm in size (pelletdistribution effect). The amount of active substance is preferablydistributed over about 250 individual pellets. Moreover a pelletcomprises 0.003 mg to 0.1 mg, preferably 0.004 mg, of budesonide. Thepellets are suitably combined to give single dose units. For thispurpose they can be enclosed by any desired pharmaceutically suitableenvelope. The pellets can moreover be in the form of capsules, tablets,granules or in the form of sachets, which have been formulated in aconventional way. The pharmaceutical compositions may furthermorecomprise formulation aids such as suspending agents, stabilizers and/ordispersants.

Eudragit L and S comprise acrylic/methacrylic acid copolymers withcarboxyl groups, whereby these lacquers become soluble above pH 5.8 and6.8 respectively.

More precisely, Eudragit L is a poly(methacrylic acid, methylmethacrylate) with a molar ratio of 1:1 and a molecular weight of135,000 or a poly(ethyl acrylate, methacrylic acid) with a molar ratioof the monomeric units of 1:1 and a molecular weight of 250,000.Eudragit S is a poly(methacrylic acid, methyl methacrylate) with a molarratio of the monomeric units of 1:2 and a molecular weight of 135,000.

Eudragit RS and RL are acrylic/methacrylic acid copolymers withquaternary ammonium groups. They are insoluble but swellable and subjectto graded erosion in the pH range 1 to 7.

More precisely, Eudragit RL is a poly(ethyl acrylate, methylmethacrylate, trimethylammonioethyl methacrylate chloride) with a molarratio of the monomer units of 1:2:0.2 and a molecular weight of 150,000.Eudragit RS is a poly(ethyl acrylate, methyl methacrylate,trimethylamonioethyl methacrylate chloride) with a molar ratio of1:2:0.1 and a molecular weight of 150,000.

Active substance pellets are normally produced by stirring the activesubstance with an adhesive in an alcoholic liquid and spraying thissuspension or solution onto so-called starter pellets. These starterpellets can be any desired pharmaceutically utilizable neutral pelletssuch as sugar/corn starch pellets. It is possible where appropriate touse other auxiliaries and formulation aids known to a skilled worker.However, testing the release of active substance revealed entirelyunsatisfactory releases of active substance. Even after 4 hours insimulated intestinal fluid, less than 80% of the active substance haddissolved (see Comparative Example 1). Evidently the active substance ispartly dissolved by the said solvents and forms a coherent, sparinglysoluble layer on the pellets. This behavior is entirely unusual becauseonly 3 mg of active substance were applied to 300 mg of starter pellets(1%).

Tests with water, in which the active substance dissolved virtually notat all, also lead to unsatisfactory releases (Comparative Example 2).Surprisingly, it was possible to find the required rapid release ofactive substance by suspending the active substance in a 0:100 to 20:80alcohol:water solvent mixture and adding at least 2 parts of awater-soluble auxiliary to one part of active substance. The ratio 1part of budesonide:4 parts of α-lactose monohydrate proved particularlyadvantageous in this connection. Other auxiliaries such as sucrose,sorbitol, mannitol, monosodium citrate etc. are also suitable (Example1).

Economic considerations indicate that a release-controlling membrane onthe pellets should not amount to more than 20% of the pellet weight.

Investigations with usual lacquers resistant to gastric fluid, such ascellulose acetate phthalate, hydroxypropylmethylcellulose phthalate andEudragit L, however, showed that on testing the release of activesubstance at pH 6.8 release is too rapid even with 20% lacquer. As aconsequence of the large surface area of the pellets, the lacquer isdetached so rapidly that the release, substantiated from clinicalinvestigations, of

    ______________________________________    0 to 2 hours                pH 1.2     0% release of active                           substance    15 min      pH 6.8     max. 5% release of active                           substance    120 min     pH 6.8     min. 90% release of active                           substance    ______________________________________

was far from being reached. In all cases, the release after 15 min at pH6.8 was already more than 50%. In addition, the amount of lacquer wasunsatisfactorily high (20%).

A combination of Eudragit L with Eudragit S, which dissolves only at pH7.0, also gave unsatisfactory results. Even with a Eudragit S:Eudragit Lratio of 8:2 it was not possible to reach the requirement (max. 5% after15 min) (Comparative Example 3).

Addition of a third component, Eudragit RS, leads, with economicallyjustifiable amounts of lacquer (about 10 to 15%), to a distinctreduction in the release of active substance at pH 6.8. With an amountof lacquer of 13.5% (Eudragit L:Eudragit S:Eudragit RS 46.5:46.5:7) atpH 6.8 there is release only of 5 to 10% within the first 15 minutes.Although increasing the Eudragit RS content to 12% achieves a reductionin release to below 5% after 15 minutes, surprisingly there is so greata reduction in the detachment of lacquer that after 120 min only about70% is released (Examples 2 and 3). It is thus evident that everyreduction of release of active substance in the first 15 min changes thenature of the lacquer membrane in such a way that the biologicallyimportant release requirement of min. 90% after 120 min can no longer beachieved. The above release profile which is necessary for medicalreasons can, surprisingly, be achieved by a separate, second lacquermembrane.

For this purpose, the pellets produced as in Example 4 receive a secondlacquer membrane comprising Eudragit RL. The amount is 0.1-3% (based onthe lacquered active substance pellets). As Example 4 proves, therelease of active substance after 15 minutes is 0%, but is already 81%after 60 minutes and 96% after 120 minutes. The second lacquer membraneis essential to the invention because it suppresses the release after 15minutes to 0% with an inconsiderable reduction in the release after 120minutes. This complicated release profile cannot be achieved with one ofthe mixtures shown in the comparative examples. The second lacquermembrane consists of Eudragit RL or RS or of mixtures of the twolacquers.

The said lacquers are dissolved as usual in alcohols such as ethanol,isopropanol and in acetone. As a rule, about 10% of plasticizer (basedon lacquer dry matter) such as triacetin or dibutyl phthalate and talcare added to the lacquer solutions. The lacquer suspensions are, as arule, sprayed using two-component nozzles in suitable coating equipment.

The production sequence is depicted in the flow diagram shown in FIG. 1.In principle, it comprises the adsorption of the active substance oninert starter pellets, the coating of the pellets with ph-dependentsoluble or insoluble lacquers and the encapsulation of the pellets.

Variations in content of the order of 5 to 10% from batch to batch mustbe expected in the production of the active substance pellets. Thesevariations make it necessary for the active substance content of thepellets to be determined before the encapsulation and to be taken intoappropriate account when filling the capsules. The weight of capsulefilling in a batch is calculated from the result of the budesonidecontent determinations on every batch of pellets. The weight is adjustedif required with the appropriate amount of neutral pellets.

The invention is explained in detail by means of the following examples.

Comparative Example 1

The release of active substance takes place under the followingconditions:

Paddle method (USP XX II)

75 rpm, 37±0.5 degrees Celsius

Media

pH 1.2: 2 g of sodium chloride and 6.4 g of 37% strength HCl per 1000 mlof water

pH 6.8: 28 g of disodium hydrogen phosphate, anhydrous, and 4.34 g ofcitric acid per 1000 ml of water; adjusted to pH 6.8. 1.0 g of Myrj 53is dissolved in 1000 ml of the buffer.

Composition of the pellets

    ______________________________________    neutral pellets      (1)   10.0 kg    Plasdone K 25        (2)   0.1 kg    talc                 (3)   0.4 kg    budesonide, micron.  (4)   0.1 kg                               10.6 kg    ______________________________________

Component 2 is dissolved in 8 kg of 8:2 ethanol/water, and components 3and 4 are suspended using an Ultra-Turrax. The suspension is sprayedonto the rotating neutral pellets in a pan by means of a two-componentnozzle.

Release of active substance

    ______________________________________                  pH 1.2                        pH 6.8    ______________________________________    15 min          24%     18%    30 min          45%     43%    60 min          59%     61%    120 min         67%     69%    180 min         74%     73%    ______________________________________

Comparative Example 2

Budesonide active substance pellets are produced as in ComparativeExample 1 with the difference that the active substance and the talc aresuspended in an aqueous Plasdone solution (about 8 kg) and sprayed ontothe neutral pellets.

Release of active substance

    ______________________________________                pH 6.8    ______________________________________           15 min 34%           30 min 48%           60 min 58%           120 min                  65%           180 min                  69%           Result:    ______________________________________

Comparative Examples 1 and 2 show that the medically necessary releaseof minutes. 90% after 120 minutes at pH 6.8 cannot be achieved withthese pellets.

EXAMPLE 1

    ______________________________________    neutral pellets       (1)   10.0 kg    Plasdone K 25         (2)   0.1 kg    talc                  (3)   0.4 kg    α-lactose monohydrate                          (4)   0.4 kg    budesonide, micronized                          (5)   0.1 kg    ______________________________________

Component 2 is dissolved in 3.3 kg of 9:1 water/ethanol, and components3 to 5 are suspended using an Ultra-Turrax. The suspension is sprayedonto the neutral pellets in a rotating pan using a two-component nozzle.

Release of active substance

    ______________________________________                  pH 1.2                        pH 6.8    ______________________________________    15 min          89.6%   88.7%    30 min          98.1%   98.4%    60 min          99.3%   98.8%    120 min         99.5%   99.1%    ______________________________________

Result

The active substance pellets released the active substance with optimalrapidity independently of the pH.

Comparative Example 3

Active substance pellets from Example 1 are sprayed as follows:

    ______________________________________    active substance pellets                          (1)   5.50 kg    Eudragit S            (2)   0.97 kg    Eudragit L            (3)   0.24 kg    dibutyl phthalate     (4)   0.12 kg    talc                  (5)   1.00 kg    ______________________________________

Components 2, 3, 4 are dissolved in 15 kg of 95:5 isopropanol/water, andtalc is suspended in.

This lacquer suspension is sprayed onto 5.5 kg of active substancepellets in a rotating pan (amount of lacquer 22% based on starterpellets).

Release of active substance

    ______________________________________    pH 1.2                 pH 6.8    ______________________________________     60 min    0%          15 min  42%    120 min    0%          30 min  83%                           60 min  96%    ______________________________________

The pellets are first stirred at pH 1.2 for 120 min and then transferredquantitatively through a screen into buffer solution pH 6.8.

Result

The required release of max. 5% after 15 min at pH 6.8 cannot beachieved with economically justifiable amounts of lacquer (8:2 EudragitS:Eudragit L lacquer combination).

EXAMPLE 2

5.5 kg of active substance pellets from Example 1 are sprayed with thefollowing lacquer combination exactly as in Comparative Example 3:

    ______________________________________    Eudragit S      0.345 kg    Eudragit L      0.345 kg    Eudragit RS     0.052 kg    dibutyl phthalate                    0.070 kg    talc            0.075 kg    ______________________________________

The lacquer components (Eudragit S:Eudragit L:Eudragit RS 46.5:46.5:7)are dissolved in 8.5 kg of 9:1 isopropanol/water and the subsequentprocedure is as in Comparative Example 3.

Release of active substance

    ______________________________________    pH 1.2                pH 6.8    ______________________________________     60 min  0%           15 min    9.5%    120 min  0%           30 min   43.0%                          60 min   75.0%                          120 min  96.5%    ______________________________________

Result

The release of active substance after 15 min at pH 6.8 is distinctlyreduced compared with Comparative Example 3 but does not yet reach therequired value of max. 5% after 15 minutes at pH 6.8. The release after120 minutes is above the tolerance limit (minutes. 90% after 120minutes).

EXAMPLE 3

Active substance pellets from Example 1 are sprayed with the followinglacquer combination exactly as in Example 2:

    ______________________________________    Eudragit S            0.327  kg    Eudragit L            0.327  kg    Eudragit RS           0.089  kg    dibutyl phthalate     0.070  kg    talc                  0.075  kg    ______________________________________

The lacquer components (Eudragit S:Eudragit L:Eudragit RS 44:44:12) aredissolved in 8.5 kg of 9:1 isopropanol/water and the subsequentprocedure is as in Example 2.

Release of active substance

    ______________________________________    pH 1.2                pH 6.8    ______________________________________     60 min   0%           15 min  2.4%    120 min   0%           30 min 26.4%                           60 min 56.3%                          120 min 78.1%                          180 min 89.8%    ______________________________________

Result

Increasing the Eudragit RS content to 12% pushes the release below 5%after 15 minutes at pH 6.8, but the release requirement after 120minutes (minutes. 90%) is clearly not met.

EXAMPLE 4

5.5 kg of active substance pellets from Example 1 are sprayed with thefollowing lacquer layers exactly as in Example 3:

    ______________________________________    Lacquer layer I    Eudragit S      0.304 kg    Eudragit L      0.304 kg    Eudragit RS     0.052 kg    dibutyl phthalate                    0.065 kg    talc            0.065 kg    ______________________________________

The lacquer combination (Eudragit S:Eudragit L:Eudragit RS 46:46:8) isdissolved in 7.6 kg of 9:1 isopropanol/water and the subsequentprocedure is as in Comparative Example 3. The amount of lacquer is 12%.

Release of active substance

    ______________________________________    pH 1.2                 pH 6.8    ______________________________________     60 min     0%         15     min  14.4%    120 min     0%         30     min  49.0%                           60     min  84.0%                           120    min  98.4%    Lacquer layer II    Eudragit RL            0.060  kg    dibutyl phthalate      0.070  kg    talc                   0.100  kg    ______________________________________

Eudragit RL is dissolved in 3.66 kg of 9:1 isopropanol/water and theplasticizer and talc are added by means of an Ultra-Turrax. The lacquersuspension is sprayed onto the pellets provided with lacquer layer I ina pan.

Release of active substance

    ______________________________________    pH 1.2                 pH 6.8    ______________________________________     60 min   0%            15 min  0%    120 min   0%            30 min 28%                            60 min 81%                           120 min 97%    ______________________________________

Result

The second lacquer layer (0.92% Eudragit RL based on lacquered activesubstance pellets) reduces the release after 15 minutes at pH 6.8 to 0%as required while meeting the release requirement (minutes. 90% at 120minutes). The combination of two lacquer layers proves to beconsiderably better than lacquer combinations of the lacquers mentionedfor controlling release.

EXAMPLE 5

Active substance pellets are produced as in Example 1 containing threetimes the amount of active substance.

    ______________________________________    neutral pellets        10.0   kg    Plasdone               0.1    kg    talc                   0.4    kg    α-lactose monohydrate                           1.2    kg    budeuonide, micron.    0.3    kg                           12.0   kg    ______________________________________

These pellets are sprayed with the following lacquer layers asdescribed:

    ______________________________________    Lacquer layer I    Eudragit S            0.49   kg    Eudragit L            0.49   kg    Eudragit RL           0.22   kg    dibutyl phthalate     0.12   kg    talc                  0.18   kg    Lacquer layer II    Eudragit RS           0.081  kg    dibutyl phthalate     0.01   kg    talc                  0.01   kg    ______________________________________

Release of active substance

    ______________________________________    pH 1.2                pH 6.8    ______________________________________     60 min   0%           15 min  1.8%    120 min   0%           60 min 75.3%                          120 min 92.9%    ______________________________________

Result

The medically necessary release profile is likewise obtained with thelacquer combination (lacquer layer I) of Eudragit S:Eudragit L:EudragitRL 41:41:18 (amount of lacquer 10%) and lacquer layer II with 0.59%Eudragit RS.

EXAMPLE 6

3 mg budesonide capsules

    ______________________________________    Composition          mg/capsule  function    ______________________________________    1)    budesonide, micr.                         3.0         active                                     substance    2)    neutral pellets                         300.0       starter          1.0-1.18 mm                pellets    3)    lactose monohydrate                         12.0        filler    4)    Plasdone K25 average                         0.9         binder          MW 25,000    5)    Eudragit L     18.3        lacquer    6)    Eudragit S     18.3        lacquer    7)    Eudragit RS    3.0         lacquer    8)    Eudragit RL    2.1         lacquer    9)    dibutyl phthalate                         4.2         plasticizer    10)   talc           44.7        release agent          capsule contents                         406.5    11)   hard gelatin capsule                         77.0          size I    12)   water*, purified           approx. 69 mg    13)   isopropanol*               approx                                     409 mg          Total capsule weight                         483.5    ______________________________________     *volatile constituents

EXAMPLE 7

    ______________________________________    lacquered active substance    pellets from Example 6 (1)   1.35 kg    microcrystalline cellulose                           (2)   4.00 kg    lactose, directly    tablettable            (3)   1.60 kg    silicon dioxide        (4)   0.10 kg    magnesium stearate     (5)   0.10 kg                                 7.15 kg    ______________________________________

Components (2) to (4) are passed through a screen with a mesh width of1.0 mm, and then component (1) is added and mixing is carried out for 10minutes. Subsequently component (5) is added, and mixing is againcarried out for 5 minutes. The mixture is compressed to tablets with adiameter of 13 mm. The weight of the tablet is 715 mg, and thebudesonide content is 1 mg. The tablet disintegrates after 2 minutes,releasing the lacquered budesonide active substance pellets.

EXAMPLE 8

    ______________________________________    lacquered active substance    pellets from Example 6                          (1)   8.13 kg    sorbitol instant granules                          (2)   40.00 kg    sodium carboxy-    methylcellulose       (3)   2.15 kg    citric acid           (4)   0.90 kg    lemon flavor          (5)   0.82 kg                                52.00 kg    ______________________________________

Components (2) to (4) are passed through a screen with a mesh width of1.0 mm and mixed together with component (1) for 15 minutes. The mixtureis packed in sachets each containing 2.6 g.

Before use, a sachet is suspended in a glass of water with stirring. Theresult is a pleasant-tasting drink in which there is scarcely anysedimentation of pellets, as a consequence of the increase in viscosity.A sachet contains 406.5 mg of pellets, which corresponds to 3 mg ofbudesonide.

EXAMPLE 9

375,000 hard gelatin capsules each containing 3 mg of budesonide wereproduced using the budesonide pellets according to the invention. Therelease profile was determined as in Comparative Example 1. Thefollowing values were obtained:

    ______________________________________    2h              pH 1.2   0%    15 min          pH 6.8   0%    30 min          pH 6.8  -55%    60 min          pH 6.8  >90%    ______________________________________

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the inventions will suggestthemselves to those skilled in the art.

We claim:
 1. Budesonide pellets with a controlled release profile, wherethe release of active substance is 0% after 15 minutes and at least 90%after 120 minutes, which pellets comprise, from the inside to theoutside:a) sugar spheres; b) an active substance layer comprisingmicronized budesonide and one or more water-soluble auxiliaries; c) afirst lacquer layer comprising 80 to 97% of at least one lacquer whichis insoluble in gastric fluid and soluble in intestinal fluid and 3 to20% of at least one lacquer which is insoluble in gastric and intestinalfluids; and, d) a second lacquer consisting of 100% of at least onelacquer which is insoluble in gastric and intestinal fluids.
 2. Thebudesonide pellets of claim 1 which, from the inside to the outside,comprise:a) 75 to 95% by weight of sugar spheres; b) 0.4 to 20% byweight of an active substance layer comprising micronized budesonide andone or more water-soluble auxiliaries; c) 4 to 16% by weight of a firstlacquer layer comprising 80 to 97% of at least one lacquer which isinsoluble in gastric fluid and soluble in intestinal fluid and 3 to 20%of at least one lacquer which is insoluble in gastric and intestinalfluids; and, d) 0.1 to 3% by weight of a second lacquer layer consistingof 100% of at least one lacquer which is insoluble in gastric andintestinal fluids, in each case based on lacquered active substancepellets.
 3. The pellets of claim 1 wherein the one or more water-solubleauxiliaries is selected from the group consisting of α-lactosemonohydrate, sucrose, sorbitol, mannitol, and monosodium citrate.
 4. Thepellets of claim 1 wherein the budesonide content is 0.1 to 5% by weightbased on lacquered active substance pellets.
 5. The pellets of claim 1wherein the particle size of the micronized budesonide is in the rangeof from 5 to 25 μm.
 6. The pellets of claim 1 in the form of capsules,tablets or granules.
 7. A process for producing budesonide pellets witha controlled release profile wherein the release of active substance is0% after 15 minutes and at least 90% after 120 minutes, comprising:a)suspending micronized budesonide as an active substance in a solventmixture consisting of alcohol:water from 0:100 to 20:80 with theaddition of one or more water-soluble auxiliaries to form a suspension;b) the spraying the suspension onto sugar spheres; c) drying the sprayedsugar spheres; d) spraying the dried pellets with a first lacquersuspension consisting of 80 to 97% of at least one lacquer which isinsoluble in gastric fluid and soluble in intestinal fluid and 3 to 20%of at least one lacquer which is insoluble in gastric and intestinalfluids; e) drying the sprayed pellet; f) spraying onto the pellets ofe), a second lacquer suspension consisting of 100% of at least onelacquer which is insoluble in gastric and intestinal fluids; and, g)drying the active substance pellets.
 8. The process of claim 7, whereinabout 0.1-5 wt.-% of micronized budesonide is suspended in the solventmixture and 4 to 16 wt.-% of the first lacquer suspension, based onlacquered active substance pellets, is sprayed on the sugar spheres, and0.1 to 3 wt.-%, based on lacquered active substance pellets of thesecond lacquer is sprayed on, and the active substance pellets aredried.
 9. The process of claim 7 wherein the water-soluble auxiliary isat least one selected from the group consisting of α-lactosemonohydrate, sucrose, sorbitol, manitol and monosodium citrate.
 10. Theprocess of claim 7 wherein the budesonide content is about 0.1-5 wt.-%based on lacquered active substance pellets.
 11. The process of claim 7wherein the particle size of the micronized budesonide is in the rangeof from 5 to 25 μm.
 12. The process of claim 7 wherein a suitable amountof pellet is packed in hard gelatin capsules or, with suitableauxiliaries, in sachets or compressed with suitable auxiliaries totablets.
 13. The pellets of claim 1, wherein the first lacquer layercomprises (i) a poly(methacrylic acid, methyl methacrylate) with a molarratio of 1:1 and a molecular weight of 135,000 or a poly(ethyl acrylate,methacrylic acid) with a molar ratio of monomeric units of 1:1 and amolecular weight of 250,000; (ii) a poly(methacrylic acid, methylmethacrylate) with a molar ratio of monomeric units of 1:2 and amolecular weight of 135,000; (iii) a poly(ethylacrylate,methylmethacrylate, trimethyl ammonioethyl methacrylate chloride) with amolar ratio of 1:2:0.2 and a molecular weight of 150,000; and (iv) apoly(ethylacrylate, methyl methacrylate trimethyl ammonioethylmethacrylate chloride) with a molar ratio of 1:2:0.1 and a molecularweight of 150,000.
 14. The pellets of claim 1, wherein the secondlacquer layer comprises a poly(ethylacrylate, methylmethacrylatetrimethyl ammonioethyl methacrylate chloride) with a molar ratio of1:2:0.2 and a molecular weight of 150,000 and a poly(ethylacrylate,methylmethacrylate, trimethyl ammonioethyl methacrylate chloride) with amolar ratio of 1:2:0.1 and a molecular weight of 150,000.
 15. Thepellets of claim 1, wherein the first lacquer layer comprises (a) from20% to 77% of a poly(methacrylic acid, methyl methacrylate) with a molarratio of 1:1 and a molecular weight of 135,000 or a poly(ethylacrylate,methacrylic acid) with a molar ratio of monomeric units of 1:1 and amolecular weight of 250,000; (b) from 20% to 77% of a poly(methacrylicacid, methyl methacrylate) with a molar ratio of monomeric units of 1:2and a molecular weight of 135,000, and (c) from 3% to 20% of apoly(ethylacrylate, methylmethacrylate, trimethyl ammonioethylmethacrylate chloride) with a molar ratio of 1:2:0.2 and a molecularweight of 150,000 and a poly(ethylacrylate, methylmethacrylate trimethylammonioethyl methacrylate chloride) with a molar ratio of 1:2:0.1 and amolecular weight of 150,000 wherein the total amount of (a) and (b),when combined, is 80% to 97%.
 16. The pellets of claim 1, wherein thesecond layer comprises from 0% to 100% of a poly(ethylacrylate,methylmethacrylate, trimethyl ammonioethyl methacrylate chloride) with amolar ratio of 1:2:0.2 and a molecular weight of 150,000 and from 100%to 0% of a poly(ethylacrylate, methyl methacrylate trimethylammonioethyl methacrylate chloride) with a molar ratio of 1:2.0:0.1 anda molecular weight of 150,000.
 17. The process of claim 7, wherein thefirst lacquer layer comprises at least one of (i) a poly(methacrylicacid, methyl methacrylate) with a molar ratio of 1:1 and a molecularweight of 135,000 or a poly-(ethyl acrylate, methacrylic acid) with amolar ratio of monomeric units of 1:1 and a molecular weight of 250,000;(ii) a poly(methacrylic acid, methyl methacrylate) with a molar ratio ofmonomeric units of 1:2 and a molecular weight of 135,000; (iii) apoly(ethylacrylate, methylmethacrylate, trimethyl ammonioethylmethacrylate chloride) with a molar ratio of 1:2:0.2 and a molecularweight of 150,000; and (iv) a poly(ethylacrylate, methyl methacrylate,trimethyl ammonioethyl methacrylate chloride) with a molar ratio of1:2:0.1 and a molecular weight of 150,000.
 18. The process of claim 7,wherein the second lacquer suspension comprises at least one ofpoly(ethylacrylate, methyl methacrylate, trimethyl ammonioethylmethacrylate chloride) with a molar ratio of 1:2:0.2 and a molecularweight of 150,000 and poly(ethylacrylate, methylmethacrylate, trimethylammonioethyl methacrylate chloride) with a molar ratio of 1:2:0.1 and amolecular weight of 150,000.
 19. The process of claim 7, wherein thefirst lacquer suspension comprises (a) from 20% to 77% of apoly(methacrylic acid, methyl methacrylate) with a molar ratio of 1:1and a molecular weight of 135,000 or a poly(ethylacrylate, methacrylicacid) with a molar ratio of monomeric units of 1:1 and a molecularweight of 250,000; (b) from 20% to 77% of a poly(methacrylic acid,methyl methacrylate) with a molar ratio of monomeric units of 1:2 and amolecular weight of 135,000, and (c) from 3% to 20% of apoly(ethylacrylate, methylmethacrylate, trimethyl ammonioethylmethacrylate chloride) with a molar ratio of 1:2:0.2 and a molecularweight of 150,000 and a poly(ethylacrylate, methylmethacrylate,trimethyl ammonioethyl methacrylate chloride) with a molar ratio of1:2:0.1 and a molecular weight of 150,000 wherein the total amount of(a) and (b), when combined, is 80% to 97%.
 20. The process of claim 7,wherein the second lacquer suspension comprises from 0-100% of apoly(ethylacrylate, methylmethacrylate, trimethyl ammonioethylmethacrylate chloride) with a ratio of 1:2.0:0.2 and a molecular weightof 150,000 and from 100% to 0% of a poly(ethylacrylate, methylmethacrylate, trimethyl ammonioethyl methacrylate chloride) with a molarratio of 1:2.0:0.1 and a molecular weight of 150,000.